| Protocol No: | ECCT/12/09/03 | Date of Protocol: | 11-10-2012 |
| Study Title: | Reduction of EArly mortaLITY in HIV-infected adults and children starting antiretroviral therapy |
| Study Objectives: |
To identify effective, safe and acceptable interventions to reduce early mortality (all-cause) in HIV-infected individuals initiating ART at low CD 4 counts.
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| Laymans Summary: |
What is the problem?
Many people affected by HIV/AIDS are still starting antiretroviral (ARV) treatment later than is recommended. This is often because they did not know they had HIV until they became sick. It means that their immune system is already very compromised, and they are at risk of death from infections. Unfortunately, amongst those with a severely compromised immune system, the risk of a variety of infections such as TB, fungi or those caused by bacteria remains high for several months even after starting ARVs. It has also been observed that those with poor nutritional status have an increased risk of death after starting ARVs compared to people with a better nutritional status.
What questions are we trying to answer?
This study is a trial that will assess three different potential means of preventing death in people with HIV and a severely compromised immune system who are starting ARVs, The three interventions are: four ARV drugs instead of three; extra drugs to prevent TB, fungal and bacterial infections; and enhanced nutritional support.
Where is the study taking place, how many people does it involve and how are they selected?
The study is taking place at 9 clinics in 4 countries: Kenya, Uganda, Zimbabwe and Malawi. In Kilifi, we aim to recruit up to 300 people. They will be selected if they are adults or children who are 5 years old or more, eligible to start ART and have very low CD4 counts (less than 100) indicating a severely compromised immune system. Women who are pregnant or those who have previously received ARVs will not be included.
What does the study involve for those who are in it?
Initially, information will be given about the study and consent sought for a screening blood test to confirm that the person is eligible. Then, detailed information about the study will be given, and consent to participate sought. The person will randomly receive 0,1,2, or 3 of the interventions in addition to standard care according to national guidelines. Participants will be reviewed in the clinic monthly. Blood tests will be taken at baseline, 4, 12, 24, 36 and 48 weeks to monitor progress and check for any adverse effects, a total of 8 to 10ml (2 teaspoons) each time. The study activities will finish after 48 weeks when the person will return to normal standard care.
What are the benefits and risks/costs of the study for those involved?
There are no direct benefits to taking part. However, participants will receive a high standard of care including supportive treatment and investigation. The cost of fares to attend follow up visits will be met by the study team. The risks are minor discomfort at blood sampling, the potential for toxicity from the additional drugs, and the potential for compliance problems with an additional pill burden.
How will the study benefit society?
The results of this trial may lead to improved protocols for treating people with HIV that could save lives in the future.
When does the study start and finish?
The study is expected to begin in the third quarter of 2012 and continue for 3 years. Each participant will be involved for 48 weeks
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| Abstract of Study: | A 2x2x2 open-label factorial multi-centre trial, conducted in 9 centres in 4 countries (Kenya, Malawi, Uganda, Zimbabwe) involving 1800 HIV-infected patients (approximately 300 in Kilifi) including adults, adolescents and children aged 5 years or older with low CD4 counts, about to initiate combination antiretroviral therapy (ART). The trial will examine three interventions which aim to reduce early mortality following ART initiation in previously untreated patients presenting late with very low CD4 counts:
(i) increasing the potency of ART with a 12 week induction period using 4 antiretroviral drugs from 3 classes (ii) augmented prophylaxis against opportunistic/bacterial infections and helminths for 12 weeks (iii) macronutrient intervention using ready-to-use supplementary food for 12 weeks.
Each intervention will be compared with standard of care, which is normally to initiate ART with 3 drugs from 2 classes, together with cotrimoxazole prophylaxis, with macronutrient intervention only for those with very low BMI or weight-for-height.
Participants will be enrolled at the comprehensive care and research clinic (CCRC) in Kilifi, at presentation or referral from the wards, and will be randomised over a period of 1.5-2 years. Each intervention will be administered in addition to standard of care for 12 weeks. All participants will be followed for 48 weeks in the trial. The start of the trial will be mid-2012 and its overall duration will be 3 years.
The primary outcome is all-cause mortality over the first 24 weeks after starting ART. Secondary outcomes include 48 week mortality (all-cause); Safety (serious adverse events, grade 4 adverse events; adverse events leading to modification of ART or other study drugs) Endpoints relating to the specific mechanisms of action of each intervention ( anti-HIV: CD4 cell counts; anti-infection: incidence of TB, cryptococcal and candida disease, severe bacterial infections; nutritional: BMI, weight and body fat assessed by bioimpedance analysis (BIA), height (in children), grip strength); Hospital inpatient episodes and adherence to ART and acceptability of each strategy.
To assess these end point these will neccessitate:
The trial will involve 8 – 10 mls of blood taken at standard clinic visits to be divided as follows: haematology/lymphocyte subsets/immunophenotyping (1.5 – 2mls); Biochemistry (1.5 mls) and the remaining 6.5 – 7mls for plasma storage. Stools sample will be stored at each visit. Besides investigation for clinical care (e.g. microbial cultures) additional 8-10 mls blood will be drawn and plasma (5-7mls) will be stored during acute admission.
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